Inland lakes are socially and ecologically important components of many regional landscapes. Exploring lake responses to plausible future climate scenarios can provide important information needed to inform stakeholders of likely effects of hydrologic changes on these waterbodies in coming decades. To assess potential climate effects on lake hydrology, we combined a previously published spatially explicit, processed-based hydrologic modeling framework implemented over the lake-rich landscape of the Northern Highlands Lake District within the United States with an ensemble of climate change scenarios for the 2050s (2041–2070) and 2080s (2071–2100). Model results quantify the effects of climate change on water budgets and lake stage elevations for 3692 lakes and highlight the importance of landscape and hydrologic setting for the response of specific lake types to climate change. All future climate projections resulted in loss of ice cover and snowpack as well as increased evaporation, but variability in climate projections (warmer conditions, wet winters combined with wet or dry summers) interacted with lake characteristics and landscape position to produce variable lake hydrologic changes. Water levels for drainage lakes (lakes with substantial surface water inflows and outflows) showed nearly no change, whereas minimum water levels for seepage lakes (minimal surface water fluxes) decreased by an average of up to 2.64 m by the end of the 21st century. Our physically based modeling approach is parsimonious and computationally efficient and can be applied to other lake-rich regions to investigate interregional variability in lake hydrologic response to future climate scenarios.